Transthyretin Amyloidosis Can Spontaneously Reverse

Transthyretin can produce amyloid, a harmful misfolded form of the protein that aggregates in the cardiovascular system and contributes to forms of heart disease. Clearing the build up of these aggregates is a work in progress. A variety of therapies entered the market in recent years, but have yet to make the leap to widespread preventative use in the broader population of older individuals. Cost is one factor. In this context, it is interesting to note a report of spontaneous reversal of transthyretin amyloidosis in a small number of individuals, likely mediated by immune clearance of amyloid, as the condition is not viewed as one in which this sort of recovery is possible.

Transthyretin amyloidosis (ATTR) is caused by amyloid deposits composed of a blood protein called transthyretin (TTR). It can be hereditary or non-hereditary ("wild-type"). The build-up of these protein deposits in the heart is called ATTR amyloid cardiomyopathy (ATTR-CM). Current treatments aim to relieve the symptoms of heart failure, but do not tackle the amyloid, although a number of "gene-silencing" therapies are currently being trialed which reduce TTR protein concentration in the blood and thereby slow ongoing amyloid formation.

Advances in imaging techniques has meant substantially more people being diagnosed with the disease than was the case 20 years ago. Previously, diagnosis needed a biopsy (involving tissue taken from the heart). The imaging techniques also mean the burden of amyloid on the heart, and consequently the progression of the disease, can be more precisely monitored, making it easier to detect cases where the condition has reversed, rather than merely remaining stable. The latest study began when one man aged 68 reported his symptoms improving. This prompted the research team to look through records of 1,663 patients diagnosed with ATTR-CM. Out of these patients, two more cases were identified.

The three men's recoveries were confirmed via blood tests, several imaging techniques, and, for one patient, an assessment of exercise capacity. Scans showed heart structure and function had returned to a near-normal state and amyloid had almost completely cleared. An in-depth look at the records and assessments for the rest of the 1,663 patient cohort indicated that these three patients were the only ones whose condition had reversed.

One of the three men underwent a heart muscle biopsy that revealed an atypical inflammatory response surrounding the amyloid deposits (including white blood cells known as macrophages), suggesting an immune reaction. No such inflammatory response was detected in 286 biopsies from patients whose disease had followed a normal progression. Investigating this further, the researchers found antibodies in the three patients that bound specifically to ATTR amyloid deposits in mouse and human tissue and to synthetic ATTR amyloid. No such antibodies were present in 350 other patients in the cohort with a typical clinical course. If these antibodies could be harnessed, they could be combined with new therapies being trialed that suppress TTR protein production, enabling clinicians to clear away amyloid as well as preventing further amyloid deposition.

Link: https://www.ucl.ac.uk/news/2023/jun/devastating-heart-condition-can-be-reversed-study-shows-first-time